CDC-48/p97 Coordinates CDT-1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication

Andre Franz, Michael Orth, Paul A. Pirson, Remi Sonneville, J. Julian Blow, Anton Gartner, Olaf Stemmann, Thorsten Hoppe

    Research output: Contribution to journalArticle

    52 Citations (Scopus)

    Abstract

    Faithful transmission of genomic information requires tight spatiotemporal regulation of DNA replication factors. In the licensing step of DNA replication, CDT-1 is loaded onto chromatin to subsequently promote the recruitment of additional replication factors, including CDC-45 and GINS. During the elongation step, the CDC-45/GINS complex moves with the replication fork; however, it is largely unknown how its chromatin association is regulated. Here, we show that the chaperone-like ATPase CDC-48/p97 coordinates degradation of CDT-1 with release of the CDC-45/GINS complex. C. elegans embryos lacking CDC-48 or its cofactors UFD-1/NPL-4 accumulate CDT-1 on mitotic chromatin, indicating a critical role of CDC-48 in CDT-1 turnover. Strikingly, CDC-48(UFD-1/NPL-4)-deficient embryos show persistent chromatin association of CDC-45/GINS, which is a consequence of CDT-1 stabilization. Moreover, our data confirmed a similar regulation in Xenopus egg extracts, emphasizing a conserved coordination of licensing and elongation events during eukaryotic DNA replication by CDC-48/p97.

    Original languageEnglish
    Pages (from-to)85-96
    Number of pages12
    JournalMolecular Cell
    Volume44
    Issue number1
    DOIs
    Publication statusPublished - 7 Oct 2011

    Keywords

    • XENOPUS EGG EXTRACTS
    • UBIQUITIN-SELECTIVE CHAPERONE
    • AAA ATPASE CDC48/P97
    • CAENORHABDITIS-ELEGANS
    • CELL-CYCLE
    • C-ELEGANS
    • S-PHASE
    • PROTEIN-DEGRADATION
    • GENOME STABILITY
    • CDC45

    Cite this

    Franz, Andre ; Orth, Michael ; Pirson, Paul A. ; Sonneville, Remi ; Blow, J. Julian ; Gartner, Anton ; Stemmann, Olaf ; Hoppe, Thorsten. / CDC-48/p97 Coordinates CDT-1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication. In: Molecular Cell. 2011 ; Vol. 44, No. 1. pp. 85-96.
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    CDC-48/p97 Coordinates CDT-1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication. / Franz, Andre; Orth, Michael; Pirson, Paul A.; Sonneville, Remi; Blow, J. Julian; Gartner, Anton; Stemmann, Olaf; Hoppe, Thorsten.

    In: Molecular Cell, Vol. 44, No. 1, 07.10.2011, p. 85-96.

    Research output: Contribution to journalArticle

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    AU - Franz, Andre

    AU - Orth, Michael

    AU - Pirson, Paul A.

    AU - Sonneville, Remi

    AU - Blow, J. Julian

    AU - Gartner, Anton

    AU - Stemmann, Olaf

    AU - Hoppe, Thorsten

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    N2 - Faithful transmission of genomic information requires tight spatiotemporal regulation of DNA replication factors. In the licensing step of DNA replication, CDT-1 is loaded onto chromatin to subsequently promote the recruitment of additional replication factors, including CDC-45 and GINS. During the elongation step, the CDC-45/GINS complex moves with the replication fork; however, it is largely unknown how its chromatin association is regulated. Here, we show that the chaperone-like ATPase CDC-48/p97 coordinates degradation of CDT-1 with release of the CDC-45/GINS complex. C. elegans embryos lacking CDC-48 or its cofactors UFD-1/NPL-4 accumulate CDT-1 on mitotic chromatin, indicating a critical role of CDC-48 in CDT-1 turnover. Strikingly, CDC-48(UFD-1/NPL-4)-deficient embryos show persistent chromatin association of CDC-45/GINS, which is a consequence of CDT-1 stabilization. Moreover, our data confirmed a similar regulation in Xenopus egg extracts, emphasizing a conserved coordination of licensing and elongation events during eukaryotic DNA replication by CDC-48/p97.

    AB - Faithful transmission of genomic information requires tight spatiotemporal regulation of DNA replication factors. In the licensing step of DNA replication, CDT-1 is loaded onto chromatin to subsequently promote the recruitment of additional replication factors, including CDC-45 and GINS. During the elongation step, the CDC-45/GINS complex moves with the replication fork; however, it is largely unknown how its chromatin association is regulated. Here, we show that the chaperone-like ATPase CDC-48/p97 coordinates degradation of CDT-1 with release of the CDC-45/GINS complex. C. elegans embryos lacking CDC-48 or its cofactors UFD-1/NPL-4 accumulate CDT-1 on mitotic chromatin, indicating a critical role of CDC-48 in CDT-1 turnover. Strikingly, CDC-48(UFD-1/NPL-4)-deficient embryos show persistent chromatin association of CDC-45/GINS, which is a consequence of CDT-1 stabilization. Moreover, our data confirmed a similar regulation in Xenopus egg extracts, emphasizing a conserved coordination of licensing and elongation events during eukaryotic DNA replication by CDC-48/p97.

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